The invention relates to the use of non-peptide compounds to prevent cell death characteristic of neurological disease or injury.
Calcium-dependent mechanisms have been proposed to mediate the cell death that occurs in many neurological disorders, including: Alzheimer's disease, which is characterized by degeneration of cholinergic cells in the ventral forebrain as well as of cortical and hippocampal cells; Parkinson's disease, which is characterized by degeneration of dopaminergic cells in the substantia nigra; Huntington's disease, which is characterized by a degeneration of the GABAergic (gamma amino butyric acid) cells in the basal ganglia; AIDS dementia, which involves a degeneration principally of subcortical neurons; stroke and related ischemic disorders; epilepsy; motor neuron diseases; peripheral nerve degeneration; and head and spinal cord injuries (Schanne et al., 1979, Science, 206:699; Siesjo, 1981, J. Cereb. Blood Flow Metab., 1:155; Schwarcz et al., 1984, Life Sci., 35:19; Simon et al., 1984, J. Cereb. Blood, Flow. Metab., 4:350; Ben-Ari, 1985, Neurosci., 14:375; Beal et al., Nature, 330:649; Badalamente et al., 1986, J. Hand Surg., 11-B:337; Garthwaite et al., 1986, Neurosci., 18:437-447; Choi, 1987, J. Neurosci., 7:380; Maragos et al., 1987, Trends. Neurosci., 10:65; Olney, 1987, In: Excitatory Amino Acid Transmission, T. P. Hicks, et al., Eds., Liss, pp.217; Meyer, 1989, Brain Res. Rev., 14:227; Herrling, 1989, In: The NMDA Receptor, J. C. Watkins, et al., Eds., Oxford, pp. 177; Girault et al., 1990, Trends Neurosci., 13:325; Dreyer et al., 1990, Science, 248:364).
There is converging evidence that a calcium-dependent protease activity (CAPA) may be responsible for the cellular destruction that occurs in these neuropathological states (Leonard and Salpeter, 1982, Exp. Neurol., 76L121; Smith and Amaducci, 1982, Neurochem. Res., 7:541; Iizuka et al., 1986, J. Neurosurg., 65:92; Siman et al., 1989, J. Neurosci., 9:1579). The protease Calpain I has been causally linked to neuromuscular neuropathy (Leonard et al., 1982, Exp. Neurol., 76:121), as well as to neuronal death induced by excitatory amino acids (EAA) (Siman et al., 1989, J. Neurosci., 9:1579).
Endogenous EAA include glutamate and aspartate, which normally appear to function as neurotransmitters, but are thought to be damaging when released excessively within the nervous system. Excessive release or infusion of EAA leads to calcium-related neuronal death, and may be an etiological agent in a number of degenerative neuropathologies, including Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, epilepsy, motor neuron diseases, and head injuries (Schanne et al., 1979, Science, 206:699; Schwarcz et al., 1984, Life Sci., 35:19-32; Ben-Ari, 1985, Neurosci., 14:375; Beal et al., 1986, Nature, 330:649; Badalamente et al., 1986, J. Hand Surg.,. 11-B:337; Garthwaite et al., 1986, Neurosci., 18:437; Choi, 1987, J. Neurosci., 7:380; Maragos et al., 1987, Trends, Neurosci., 10:65; Olney, 1987, In: Excitatpry Amino Acid Transmission, T. P. Hicks, D. Lodge, and H. McLennan, Eds., Liss, pp. 217; Faden et al., 1989, Science, 244:798; Herrling, 1989, In: The NMDA Receptor, J. C. Watkins et al., Eds., Oxford, pp. 177; Choi et al., 1990., Ann. Rev. Neurosci., 13:171; Girault et al., 1990, Trends Neurosci., 13:325).
Endogenous EAA toxicity may be a fundamental mechanism of cell death, mediating the ultimate neuronal destruction wrought by a multitude of injuries or diseases of the central nervous system. Because of the convergence of evidence suggesting that CAPA may be a fundamental, obligatory event underlying neuronal death in a variety of neuropathological conditions, treatments that reduce CAPA or the events leading to CAPA (such as excitatory amino acid receptor activation) could prove to have widespread use as neurotherapeutics for a diverse range of neurological disorders. For example, the non-competitive excitatory amino acid receptor antagonist, MK-801, has been shown to block both EAA- and ischemia-induced neuronal damage in vivo (Foster et al., 1987, Neurosci. Let. 76:307, Gill et al., 1987, J. Neurosci. 7:3341).